Some Brains are Resilient to Alzheimer’s Disease: We Want to Know Why

Posted July 17, 2019

Dr. Teresa Gomez-Isla’s lab is on a mission to understand why some unique individuals are able to tolerate severe amounts of the pathological hallmarks of Alzheimer’s disease, including amyloid plaques and neurofibrillary tau tangles, without experiencing dementia. In a research paper supported with a grant from Cure Alzheimer’s Fund, Dr. Gomez-Isla and her colleagues uncovered new insights into what differentiates the brains of these resilient individuals. The research was published in the journal Neurobiology of Disease and makes the case that suppression of the neuroinflammatory response may enhance resilience to dementia.

While the brains of these individuals are riddled with plaques, these rare resilient cases do not exhibit the typical patterns of synapse loss that are normally found in the brains of Alzheimer’s patients. The synapse is the junction between two nerve cells through which neurons communicate either electrically or chemically. These resilient brains provide a rare glimpse into the protective mechanisms that may be at play in individuals who would be expected to have dementia as a result of the heavy burden of plaques and tangles in their brains.

The scientists used markers to determine the levels of microglia and astrocyte activation in the resilient brains compared with the brains of the controls and the brains from individuals who had experienced dementia and Alzheimer’s disease while alive. In an interesting turn of events, the experiment revealed that resilient brains had less activation of two markers: GFAP and CD68. This finding indicated a suppressed neuroinflammatory response in the resilient brains.

Not content to simply show evidence for differences in activation between the two groups, the researchers performed an experiment that profiled 27 different cytokines in the resilient brains and the brains from those with Alzheimer’s disease. Cytokines refer to substances that are secreted by cells in the immune system and regulate other cells. Dr. Gomez-Isla uncovered that not only were the profiles of cytokines in the resilient brains different from the other groups, but the difference was the most pronounced in the entorhinal cortex. The entorhinal cortex is one of the earliest and most severely affected brain regions in Alzheimer’s disease. In the resilient brains that had the highest probability of developing Alzheimer’s disease dementia based on the severity of the plaque accumulation, the cytokine profile showed differences in levels of IL-1b, IL-6, IL13, and IL-4. This data suggests specific cytokine targets that may play a role in enhancing resilience to Alzheimer’s disease.

Teresa Gomez-Isla’s research was highlighted in Harvard Magazine:

The full results of the study are available Open Access through Science Direct: